(+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid of the Formula (II) (rosuvastatin) is known from the state of the art. Rosuvastatin has been disclosed for the first time in European Patent No. 521471 as the free acid and some pharmaceutically acceptable salts thereof, such as the calcium salt of the Formula (III)
and ammonium salt. Published International Patent Application WO 01/060804 discloses crystalline lithium, magnesium salts of rosuvastatin and crystalline salts of the compound with certain amines. In Published International Patent Applications WO 2005023779, WO 2006079611 and WO 2008036286, several different crystalline hydrate forms of rosuvastatin calcium of the Formula (III) are disclosed. International Patent Applications WO 2005051921 and WO 2008038132 are related to further salts or rosuvastatin with amines or diamines. International Patent Application WO 2005077917 discloses amorphous rosuvastatin magnesium salt. Published International Patent Application WO 2007086082 discloses the amorphous and crystalline potassium salt and the method for the preparation thereof.
Rosuvastatin zinc (2:1) salt of the Formula (I) has been disclosed for the first time in Hungarian Patent Application P0600293 and in the corresponding International Patent Application WO 2007119085. Hungarian Patent Application P070667 and the corresponding Published International Patent Application WO 2009047577 are related to further methods for the preparation of rosuvastatin zinc salt of the Formula (I), wherein rosuvastatin of the Formula (II), sodium salt thereof, an alkyl ester thereof, rosuvastatin lactone or rosuvastatin ketal ester are used as starting materials.
In the International Patent Application WO 2008015563, a method for the preparation of rosuvastatin zinc salt of the Formula (I) has been disclosed, which comprises transforming rosuvastatin tert-butylamine salt into rosuvastatin sodium salt and producing the zinc salt by reacting said rosuvastatin sodium salt with zinc ions and filtering the product from an aqueous solvent.
Hungarian Patent Application P0900019 is related to a further method for the preparation of rosuvastatin zinc salt of the Formula (I), wherein rosuvastatin zinc salt of the Formula (I) is produced directly starting from the tert-butylamine salt of rosuvastatin and isolating said product from an organic solvent.
Rosuvastatin zinc salt of the Formula (I) obtained by the methods of Hungarian Patent Applications P0600293, P070667 and P0900019 or by the method disclosed in International Patent Application WO 2008015563 is of amorphous morphology. International Patent Application PCT/HU2009/00064 is related to crystalline Form I of rosuvastatin zinc (2:1).
The quality of pharmaceutically active ingredients used in medicinal products are determined by strict criteria set forth by health authorities. Some of these criteria is related to the chemical purity and stability of the active ingredient. Further criteria apply to the quality and stability of the medicinal product. These criteria are set forth and published in pharmacopoeias. A basic condition for the issue of the marketing authorization is the compliance with the quality requirements regarding pharmaceutically active ingredients as well as medicinal products.
During the use of rosuvastatin for the manufacture of medicaments, there exists a need for obtaining the pharmaceutically active ingredient in high purity, being chemically stable and in a form which can easily be manipulated during the manufacture of the finished dosage form.
Recently a definite need has arisen in the pharmaceutical industry in order to provide reproducible manufacturing methods for obtaining pharmaceutically active ingredients in chemically and morphologically pure form. Obtaining the pharmaceutically active ingredient in homogeneous solid state is a precondition for complying with the requirements of the industrial manufacture of finished dosage forms. It is a well known fact that solid forms of the same active ingredient having different morphology may exhibit significant differences in the rate of dissolution, bioavailability and chemical stability. From the viewpoint of industrial chemical and pharmaceutical technology, it is important that different solid forms of an active ingredient can possess significantly different properties with regard to the operations of the technology, e.g. rate of filtration or drying, solubility, behaviour during tabletting. The properties mentioned above have a direct impact on the efficiency, economy, reproducibility and complexity of the industrial manufacturing process and at the same time, result in a morphologically homogeneous product.
It is generally accepted that crystalline forms of pharmaceutically active ingredients possess improved chemical stability as compared to the amorphous form. Due to the different decomposition processes during the manufacture and shelf-life of the finished dosage form, this assumption is of general importance. Therefore, manufacturers of medicinal products prefer to use crystalline forms of the active ingredients during pharmaceutical development.
Since active ingredients belonging to the group of statins are explicitly prone to decomposition (Ravi P. Shah, Vijay Kumar and Saranjit Singh, LC-MS/MS Studies on Identification and Characterization of Hydrolytic Products of Atorvastatin, Proceedings of 12th ISMAS Symposium cum Workshop on Mass Spectrometry, Mar. 25-30, 2007, Cidade de Goa, Dona Paula, Goa), there exists a definite need to provide forms of the active ingredients belonging to this group which exhibit increased chemical stability. For example, it is known that the amorphous form of atorvastatin having similar structure to rosuvastatin (i.e. both compounds share the 3,5-dihydroxy-alkanoic acid moiety) or even the morphologically non-homogeneous mixture of amorphous and crystalline forms disclosed in European Patent 409281 are less stable than crystalline forms of the same compound. Thus, development of crystalline forms I, II and IV of atorvastatin showing enhanced properties during chemical or pharmaceutical manipulations (e.g. ease of filtration) and increased stability as disclosed in Published International Patent Application WO 97/03959, initiated development work on behalf of several pharmaceutical companies resulting in the development of more than forty crystalline forms of atorvastatin.
Rosuvastatin is especially prone to decomposition resulting from exposure to light, oxygen and heat. For example, upon light exposure, decomposition products described by Astrarita and coworkers are formed even in solid state (J. Photochem. Photobiol. A. Chem. 2007, 187, 263-268).
The polymorphism of a pharmaceutically active ingredient can be exploited in several ways. As discussed above, using a crystalline form having suitable stability and impurity profile (purity) for the manufacture of a finished dosage form is of paramount importance. It is also significant that a crystalline active ingredient should have appropriate properties for manipulations of large-scale manufacturing and pharmaceutical technology on an industrial scale. However, different properties of polymorphs, e.g. dissolution rate, particle size etc. can also be exploited during the design of different finished dosage forms. A polymorph having lower dissolution rate may contribute to the properties of a delayed release dosage form, while the skilled person may appreciate a form having higher solubility or higher dissolution rate during the formulation of an immediate release dosage form.